Today the FDA issued a guidance entitled Cross Labeling Oncology Drugs in Combination Regimens (https://www.fda.gov/media/162806/download) that describes the Agency thinking on cross labeling of oncology drugs for which there is a proven benefit from their combined use. As I read the guidance a few things popped into my mind. How can one firm who owns a product get access to the data to support the combined use in another product? This issued is addressed in the guidance (see more below on this point). And second issue has to do with patent and and/or exclusivity protection issues for the drug proposed for citation in the first applicants labeling. This question was not addressed directly but we will talk about that in a bit.
The guidance document covers the procedure for cross labeling application submissions including timing for the submission as well as the issues for regulatory submissions that must be addressed. In addition, the guidance addresses the content of labeling.
On the issue of cross labeling the FDA states; “Drug approvals in oncology often build on treatment effects by adding drugs to current regimens or by combining investigational drug products in a combination regimen, creating new regimens with greater efficacy. For the purpose of this guidance, a combination regimen refers to two or more drugs that are marketed separately, where at least one of the drugs has an approved indication for the combination based upon one or more adequate and well-controlled clinical trials. Cross labeling is defined as inclusion of information in approved product labeling of two or more oncology drug products approved in a combination regimen for a specific indication.”
However, FDA also notes that the proposed labeling change will be predicated on whether “ (1) the applicant owns or has a right of reference to the data demonstrating the safety and effectiveness of the new combination regimen for treatment of an oncological disease, (2) the applicant submits an application to FDA that includes labeling for the use of the drug in this new combination regimen, and (3) the application provides evidence to support the contribution of the applicant’s drug to the overall treatment effect of the combination regimen.” This provides the answer to the first question I raised above.
The answer to the second question is a bit more elusive! One might assume that the right of reference might also include a statement from the second applicant that they have no objection to an immediate effective date for the first applicant’s product if there is a valid period of market exclusivity on their product. In the case of a patent covering the of the proposed drug use, there could be an exclusive licensing agreement between the parties or in the interest of advancing patient treatments the patent holder may choose just not to enforce the patent and inform the Agency of that decision. Be sure to check with your patent attorney on the proper path forward.
Other interesting issues that were directly addressed in the guidance include for labeling purposes the FDA recommends that the applicant drug name should be listed first in the test followed by the use of the established name (or proper name for a biologic product), not the brand name, of the second product.
In the dosage and administration section of the labeling FDA states that, “[A]lthough this section should identify the other drug or drugs in the combination regimen, in general, information should be limited to the recommended dosage for the applicant’s drug as used in the combination regimen. Dosage information for other drugs in the combination regimen should be provided by statements that refer the reader to the Prescribing Information for the other drugs, as appropriate; however, if the combination regimen dosing is complex or if the Prescribing Information for the other drugs does not contain the necessary dosing information, the recommended dosages of each drug in the combination regimen should be specified in this section.”
There are other useful recommendations such as the suggestion that applicants request and discuss their proposal for cross labeling “in a pre-new drug application/biologics license application meeting or a pre-supplemental new drug application/biologics license application meeting.”
Take a close read and understand the pitfalls of your plans. One would think that the inclusion of a cross labeling use might increase the use of each drug and would be welcomed by the two applicants. But certainly, cross labeling will improve the treatment of cancer patients and provide addition helpful information to health care practitioners in the oncology field.